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Pyruvate Kinase M2: a Metabolic Bug in Re-Wiring the Tumor Microenvironment

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  • Published:
Cancer Microenvironment

Abstract

Metabolic reprogramming is a newly emerged hallmark of cancer attaining a recent consideration as an essential factor for the progression and endurance of cancer cells. A prime event of this altered metabolism is increased glucose uptake and discharge of lactate into the cells surrounding constructing a favorable tumor niche. Several oncogenic factors help in promoting this consequence including, pyruvate kinase M2 (PKM2) a rate-limiting enzyme of glycolysis in tumor metabolism via exhibiting its low pyruvate kinase activity and nuclear moon-lightening functions to increase the synthesis of lactate and macromolecules for tumor proliferation. Not only its role in cancer cells but also its role in the tumor microenvironment cells has to be understood for developing the small molecules against it which is lacking with the literature till date. Therefore, in this present review, the role of PKM2 with respect to various tumor niche cells will be clarified. Further, it highlights the updated list of therapeutics targeting PKM2 pre-clinically and clinically with their added limitations. This upgraded understanding of PKM2 may provide a pace for the reader in developing chemotherapeutic strategies for better clinical survival with limited resistance.

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Abbreviations

ANGPT2:

Angiopoietin 2

AKT:

Serine/threonine-specific protein kinase

ALCL:

Anaplastic large cell lymphoma

ALT:

Alanine aminotransferase

AMPK:

5' AMP-activated protein kinase

ANGPTL4 :

Angiopoietin-like 4

AP-1:

Activator protein 1

C/EBPβ :

CCAAT-enhancer binding protein β

CD4:

Cluster of differentiation 4

COX-2:

Cyclooxygenase-2

CTGF:

Connective tissue growth factor

CXCL8:

C-X-C motif chemokine 8

DASA-58:

Dihydro benzodioxin sulfonyl hexahydro diazepin sulfonyl benzenamine

EGF:

Epidermal growth factor

EMT:

Epithelial–mesenchymal transition

ErbB3:

Erb-B2 Receptor tyrosine kinase 3

ERK-5:

Extracellular-signal-regulated kinase 5

FBP:

Fructose bisphosphate

FGF:

Fibroblast growth factor

FGFR1 :

Fibroblast growth factor receptor 1

GAPDH:

Glyceraldehyde 3-phosphate dehydrogenase

GLUT-1:

Glucose transporter -1

HCT-116:

Human colon cancer cell line

HIF-1α:

Hypoxia induced factor-1 alpha

HK-2:

Hexokinase-2

HMGB1:

High mobility group box-1

IFN-ϒ:

Interferon-gamma

IL-10:

Interleukin-10

IL-13:

Interleukin-13

IL-1β:

Interleukin-1β

IL-4:

Interleukin-4

IL-6:

Interleukin-6

JAK:

Janus kinase

JNK:

c-Jun N-terminal kinases

LDH:

Lactate dehydrogenase

LDH-A:

Lactate dehydrogenase-A

LOX:

Lysyl oxidase

LPS:

Lipopolysaccharide

MAPK:

Mitogen-activated protein kinases

MAP K-5:

Mitogen activated protein kinase-5

MCT-1:

Monocarboxylase transporter -1

MCT4:

Monocarboxylate transporter 4

MDM2:

Mouse double minute-2 homolog

miRNA-124:

MicroRNA-124

MMP:

Matrix metalloproteinase

MMP-2 :

Matrix metalloproteinase 2

mTOR:

Mechanistic target of rapamycin

NF-kB :

Nuclear factor kappa B

NK cells:

Natural killer cells

OXPHOS:

Oxidative phosphorylation

p53:

Tumor protein p53

PD-1:

Programmed cell death-1

PD-4:

Programmed cell death-4

PDGF:

Platelet-derived growth factor

PDGF-BB:

Ligand for platelet derived growth factor receptor

PGAM1:

Phosphoglycerate Mutase 1

PGE2:

Prostaglandin E2

PI3K:

Phosphoinositide-3-kinase

PIN1:

Peptidyl-prolyl cis-trans isomerase

PTP1B:

Tyrosine-protein phosphatase non-receptor type 1

ROS:

Reactive oxygen species

RT-PCR:

Real time-polymerase chain reaction

SAICAR:

Succino 5-amino-4-imidazole-N-succinocarboxamide ribonucleotide

SDF-1:

Stromal cell-derived factor 1

shRNA:

Small hairpin ribonucleic acid

siRNA:

Small interfering ribonucleic acid

SOD2:

Superoxide dismutase 2

STAT3:

Signal transducer and activator of transcription 3

TCA:

Tricarboxylic acid

TCR:

T cell receptor

TEPP-46:

Thieno-pyrrole-pyridazine

TGFα:

Transforming growth factor alpha

TGFβ:

Transforming growth factor beta

TH-1:

T helper cell-1

TIMP:

Tissue inhibitor of metalloproteinases

TNF-α:

Tumor necrosis factor-alpha

TRAF-5:

TNF-receptor associated factor-5

US28:

G-protein coupled receptor homolog US28

VEGF:

Vascular endothelial growth factor

vGPCR :

Viral G protein-coupled receptor

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Acknowledgments

We acknowledge the support from National Institute of Pharmaceutical Education and Research (NIPER), Ahmedabad.

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  1. Mohd Rihan and Lakshmi Vineela Nalla has equal contribution for first author.

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  1. Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Ahmedabad, Palaj, Gandhinagar, Gujarat, -382355, India

    Mohd Rihan, Lakshmi Vineela Nalla, Anil Dharavath & Amit Khairnar

  2. Department of Biotechnology, National Institute of Pharmaceutical Education and Research (NIPER), Ahmedabad, Gujarat, India

    Kiran Kalia

  3. Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), Ahmedabad, Palaj, Gandhinagar, Gujarat, -382355, India

    Amit Shard

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Rihan, M., Nalla, L.V., Dharavath, A. et al. Pyruvate Kinase M2: a Metabolic Bug in Re-Wiring the Tumor Microenvironment. Cancer Microenvironment 12, 149–167 (2019). https://doi.org/10.1007/s12307-019-00226-0

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